Methods and Compositions for Improved Delivery Devices

ABSTRACT

The present invention comprises methods and compositions for delivery devices More particularly, the present invention comprises methods and compositions for devices comprising a matrix comprising a polymer network and a non-gellable polysaccharide having oxygen and optionally active agents incorporated therein. The matrix may be formed into any desired shape for treatment of compromised tissue or for delivery of oxygen to a localized environment.

PRIOR RELATED APPLICATIONS

The present application relies on the priority of U.S. ProvisionalPatent Application No. 60/174,024, filed Dec. 30, 1999, hereinincorporated in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to the field of materials forthe delivery of gases and other agents in the treatment of compromisedtissues. More particularly, the present invention relates to treatmentof compromised tissues using devices comprising novel matrix materials,comprising either synthetic or natural materials, wherein such novelmaterials are capable of encapsulating gas bubbles to form a device thattransfers the gas to a receiving substrate.

BACKGROUND OF THE INVENTION

Damage or destruction of the blood supply to a region of living tissuequickly leads to compromised tissue. One of the critical functions of anadequate blood supply is the provision of dissolved gases to the site,such as oxygen. For example, wounds to bodily tissues are accompanied bydamage or destruction of the natural blood supply that transports oxygenand nutrients that are necessary to support the healing process.Measurements have shown that the tissue oxygen tension within the woundand surrounding damaged tissues is substantially lower than the normalblood vascular oxygen tension. Whereas the blood vascular oxygen levelof 80 to 100 mm Hg is considered normal, the wound environment may haveas little as 3 to 30 mm Hg of oxygen. Research has shown that a level of30 mm Hg or less is insufficient to support the processes of woundrepair.

Many approaches have been used in an effort to increase the amount ofoxygen delivered to compromised tissues. Initial developments toincrease the oxygen tension in the compromised tissue environmentinvolved either topical delivery of oxygen to the tissues or chambers inwhich the blood vascular oxygen tension is substantially elevated so asto also increase to tissue oxygen levels by diffusion. U.S. Pat. No.4,328,799 describes a hyperbaric oxygen chamber that was constructedsuch that it fit tightly to a portion of the anatomy. The chamber wasthen flooded with oxygen gas to higher than atmospheric pressure toincrease dissolution of oxygen for delivery to cellular processes. U.S.Pat. Nos. 4,474,571, 4,624,656, and 4,801,291 further describe variousimprovements for increasing the atmospheric oxygen concentration overthe compromised tissue environment. Although these devices are capableof functionally increasing the oxygen level over a wound site, theysuffer from the use of cumbersome apparatus, intermittent delivery ofoxygen and poor transfer of oxygen from the oxygen-rich atmosphere tothe hypoxic tissues.

Another device, disclosed in U.S. Pat. No. 4,608,041, combined deliveryof oxygen to tissues with providing an escape pathway for spent gas andwound-derived volatiles. U.S. Pat. No. 4,969,881 extended thisdevelopment to use less bulky construction by utilizing an oxygenpermeable membrane sandwich in which the interior portion was floodedwith oxygen which diffused through the wound contact membrane, but notthe upper membrane, to oxygenate tissues. This was further improved inU.S. Pat. No. 6,000,403. These devices represent improvements thatovercame much of the bulky characteristics of previous inventions butrepresent little or no improvement in the transfer of oxygen to hypoxictissues nor do they constitute improvements in wound contact matricescustomarily needed for wound care.

A different approach, used to increase the efficiency of the transfer ofoxygen and to eliminate the bulky apparatus was to use nascent oxygengeneration near the device. U.S. Pat. No. 5,407,685 provides a devicefor generating oxygen when the device was applied to a wound. The devicedisclosed is a bilayered device where each layer contains a reactantthat mixes and generates oxygen once exudate or other bodily-derivedmaterial activates the reaction. U.S. Pat. No. 5,736,582 describes thegeneration of oxygen from hydrogen peroxide for release at or near theskin surface. U.S. Pat. No. 5,855,570 similarly uses an electrochemicalreaction to convert oxygen in air to a peroxide or other reactive formof oxygen for delivery to the wound environment. U.S. Pat. No. 5,792,090uses a reservoir that contained hydrogen peroxide and a catalyst in adevice in contact with the wound, such as a hydrogel or polymeric foam.Another approach was disclosed in U.S. Pat. No. 5,086,620 in which puregaseous oxygen was dispersed by sonic energy into a liquid matrix thatwas then solidified by cooling to encapsulate the oxygen in minutebubbles.

These devices represent improvements in the delivery of topical oxygento the wound environment over the hyperbaric chamber. However, eachcarries significant limitations that have restricted the broadadaptation of the technology of topical oxygenation for care ofcompromised tissues. Previously described devices do not have a knownconcentration of oxygen and cannot function independently of atmosphericpressures or temperature to achieve effective oxygen distribution. Inaddition, the dependence upon activation by body-derived agents isunpredictable so as to make such devices impractical. Other devices areexpensive to produce and require specialized equipment. Such devicescannot be used in the production of cold set polymers that are oftenused for the construction of medical devices used for compromised tissuecare.

Compromised tissues include those tissues that have an interrupted bloodsupply or suffer from a lack of a necessary element, such as oxygen, orsuffer from the build-up of by-products, such as carbon dioxide. Onetype of compromised tissue includes wounds. Wounds are generally thoughtof as an interruption in the integrity of the skin. The outer layer ofskin surrounding the body performs an important protective function as abarrier against infection, and serves as a means of regulating theexchange of heat, fluid and gas between the body and externalenvironment. When skin is removed or damaged by being abraded, burned orlacerated, this protective function is diminished. Areas of damaged skinare conventionally protected by the application of a wound dressingwhich facilitates wound healing by acting as a skin substitute.

Compromised tissues can result from any interruption in normalbiological activity in an area. Compromised tissues result from externalinsults such as friction, abrasion, laceration, burning or chemicalirritation. Damage to such tissues may also result from internalmetabolic or physical dysfunction, including but not limited to boneprotrudence, diabetes, circulatory insufficiencies, or inflammatoryprocesses. Normally, tissue damage initiates physiological processes ofregeneration and repair. Generally, the repair process is uneventful andmay occur regardless of any intervention. However, it has been foundthat intervention and provision of needed elements aid in repair ofcompromised tissue sites. Another aspect of repair of the compromisedsite may include the control of exudates and the maintenance of anoptimal level of moisture over the compromised site, especially duringheavy exudate drainage.

The healing of compromised tissues usually progresses through distinctstages leading to the eventual restoration of the natural function. Asan example, injury to the skin initiates an immediate vascular responsecharacterized by a transient period of vasoconstriction, followed by amore prolonged period of vasodilation. Blood components infiltrate thewound site, endothelial cells are released, exposing fibrillar collagen,and platelets attach to exposed sites. As platelets become activated,components are released which initiate events of the intrinsiccoagulation pathway. At the same time, a complex series of eventstrigger the inflammatory pathways generating soluble mediators to directsubsequent stages of the healing process. These events result in atransient to prolonged period of oxygen deprivation known as hypoxia inthe tissues.

Normally, the healing process of injured tissues is uneventful and mayoccur regardless of any intervention. However, where an underlyingmetabolic condition or perpetual insult such as pressure is acontributing factor, the natural healing process may be retarded orcompletely arrested, resulting in a chronic wound. Trends in modernmedical practices have shown that the wound healing of both acute andchronic wounds may be significantly improved by clinical interventionsusing methods and materials that optimize conditions in the compromisedtissues to support the physiological processes of the progressive stagesof tissue repair. In dermal wounds, key factors in providing the optimalconditions are the prevention of scab formation and the maintenance ofan optimal level of moisture and oxygen in the wound bed. All of thesefactors may be controlled by the management of wound exudate fluid.

A common problem in the management of both acute and chronic wounds isthe maintenance of an optimal level of moisture over the wound bedduring heavy exudate drainage. This is usually, but not always, duringthe early stage of healing. Most moist wound dressing technologies suchas thin films, hydrocolloid dressings and hydrogels are typicallyoverwhelmed by exudate moisture during this heavy drainage phase.Management of moisture during heavy exudate drainage often necessitatesthe use of gauze or sponge packings that wick away excess moisture fromthe wound bed, thin film coverings that trap exudate fluid over thewound bed, calcium alginate dressings that chemically bind exudatemoisture due to the hydroscopic properties of the seaweed extract andother materials that generally restrict exposure to atmospheric oxygento the wound site.

Prior Art Dressings

Soluble collagen has been used as a subcutaneous implant for repairingdermatological defects such as acne scars, glabellar furrows, excisionscars and other soft tissue defects. Collagen has also been used in manyforms as wound dressings such as collagen sponges, as described inArtandi, U.S. Pat. No. 3,157,524 and Berg et al., U.S. Pat. No.4,320,201. However, most of these dressings are not satisfactory for thevarious types of compromised tissues. Collagen films and sponges do notreadily conform to varied wound shapes. Furthermore, some collagen wounddressings have poor fluid absorption properties and undesirably enhancethe pooling of fluids.

Another example of dressings that have been developed are hydrocolloiddressings. UK Patent No. 1,471,013 and Catania et al., U.S. Pat. No.3,969,498 describe hydrocolloid dressings that are plasma soluble, forman artificial eschar with the moist elements at the wound site, andgradually dissolve to release medicaments. Hydrocolloid dressings ingeneral, and the Catania et al. dressings in particular, are subject toa number of drawbacks. The major disadvantages of these dressingsinclude the potential to disintegrate in the presence of excess fluid atthe site, and minimal, virtually negligible, control over water and/oroxygen loss from the wound. This latter disadvantage is particularlyimportant, as excess water loss from a wound will cause an increase inheat loss from the body as a whole, potentially leading tohypermetabolism. In addition, hydrocolloid dressings require frequentdressing changes.

Some treatments for compromised tissues can cause problems at the sites.For example, thin film dressings such as those described in U.S. Pat.No. 3,645,835, maintain excessive moisture over a wound bed,contributing to the overhydration or maceration of surrounding skin.Although sponges and gauze support tissue, they require frequentchanging, and cause irritation to the compromised tissues during bodymovement and dressing removal. Calcium alginates turn into a gelatinousmass during interaction with moisture, are difficult to removecompletely, and often dehydrate a wound bed due to the hydroscopicnature of the matrix. In addition, none of these devices or materialscontribute to maintaining an appropriate level of oxygen to thecompromised tissue site. Nor do any of the currently available devicessignificantly contribute to or support the autolytic debridement phaseof wound healing.

Delivery of Active Agents

Another desirable aspect of treatment of compromised tissues is thedelivery of active agents to the site of injury. Active agents for usein compromised tissue treatment may be administered to an individual ina variety of ways. For example, active agents may be administered viamethods known to those skilled in the art, such as topically,sublingually, orally, or by injection (subcutaneous, intramuscular orintravenous). Nevertheless, there are drawbacks to many of thesemethods, and an inexpensive, reliable, localized and relativelypain-free method of administering active agents has not been provided inthe prior art.

One common method employed for the treatment of compromised tissues isthe topical application of a salve or ointment. Topical application to awound can be painful. Additionally, in the case of a deeply cavitatedwound, an excess of active agent may be required because the agent mustdiffuse through layers of necrotic tissue and newly forming epidermaltissues. Furthermore, application of topical agents to sites in theinterior of the body is highly impractical in that the topical agentsare washed off or migrate to other sites. This difficulty in deliveringthe agent may require the application of an excessive amount of theagent and preclude an accurate determination of the effective amount ofactive agent delivered.

The oral and sublingual administrations of active agents used in woundtreatment also have their drawbacks. Ingestion of an active agent mayresult in the agent having negative system-wide effects and possiblydisturbing the normal flora, or normal microbial environment, whosepresence benefits an individual. Successful absorption of the agent intothe bloodstream also depends on several factors such as the agent'sstability in gastrointestinal fluids, the pH of the gastrointestinaltract, solubility of solid agents, intestinal motility, and gastricemptying.

Injection of an active agent, a normally painful method ofadministration, may have the same negative system-wide effects as thatof an oral or sublingual administration. Yet more importantly, a dangerinherent in the injection of an active agent is that rapid removal ofthe agent is impossible once it is administered. There is also a risk oftransmission of infections and the possibility of vascular injury due tothe use of needles.

Therefore, topical, oral, sublingual and intravenous methods ofadministration pose several problems when delivering active agents forthe treatment of compromised tissues. What is needed is a method ofadministering an active agent for the treatment of compromised tissue inan effective, safe and relatively pain-free manner.

What is needed therefore, are methods and compositions for improvingtreatments for compromised tissue comprising materials having superiorexudate management capabilities, together with the ability to deliveractive therapeutic agents and participate in the management of oxygentension around such sites. Methods and compositions are needed that canprovide oxygen delivery to any size area of compromised tissue andpreferably, may also provide moisture control and delivery of otheractive agents.

In addition, there continues to be a need for a device such as a wounddressing that possesses high moisture absorption capacity, a high rateof absorption, as well as a capacity to regulate moisture at the woundbed-dressing interface. Desirably, such a wound dressing device shouldstimulate the autolytic debridement process, especially during the heavyexudating phase of wound care management.

SUMMARY OF THE INVENTION

The present invention is directed to compositions, methods and devicescomprising contact tissue materials for delivery of gases and otheractive agents. A preferred embodiment of the present invention comprisescompositions and methods for the treatment of compromised tissue. Inparticular, the present invention provides methods and compositions forproviding gases, preferably oxygen, to a site of compromised tissue orto any site where delivery of the gas is desired. Such sites include,but are not limited to, compromised tissue such as ischemic or hypoxictissue or wounds. A preferred embodiment comprises the delivery ofoxygen, which is important in methods such as keeping cells, tissues,organs or animals alive, such as in packaging of live fish, or tissueculture vessels.

Preferred embodiments of the present invention are directed to methodsand devices for treatment of compromised tissue, such as ischemic orhypoxic tissue or wounds. In one embodiment of the present invention, atissue contact material is provided that delivers oxygen locally to thewound site and may also allow for localized delivery of other activeagents and control of moisture and debridement. Such a tissue contactmaterial can be used as a wound dressing to treat wounds.

In preferred embodiments of the present invention, methods andcompositions are provided that comprise a material and a process formaking a novel material that contains an entrapped gas, preferablygaseous oxygen. The material may comprise a natural or synthetic polymerthat forms a closed cell foam structure. Preferably, the cells of thefoam are highly enriched for gaseous oxygen and the walls of the foamcells are enriched for dissolved oxygen. This material is useful as aprimary tissue contact matrix where it is desirable to transfer oxygeninto the tissue environment to increase the oxygen tension. A preferredembodiment is a polyacrylate matrix that is also flexible, elastic,conformable and highly absorbent comprising an optimal wound dressingmatrix.

Other substrates comprising formations of closed cell foams for thedelivery of oxygen to tissues are contemplated by the present invention.For example, natural polymers of gelatin, dextrose, collagen, agar andagarose possess necessary molecular architecture for the encasement ofgases such as oxygen within closed cells to form a foam-like structure.These natural polymers have the added advantage in that they areabsorbed by the tissues over time thus eliminating the requirement forremoval once the active agent has been exhausted. Therefore, thesematerials may be implanted into deep tissue sites.

Similarly other water swellable cross-linked polymers such aspolyacrylate, polymethacrylamide, polyester, polyether and polyurethanecan entrap gases such as oxygen in close cell reservoirs within thematrix for delivery to compromised tissues. Furthermore, certain waternon-swellable polymers such as silastic and silicone elastomer polymersmay entrap gases such as oxygen within closed cell structures.

The methods, compositions and devices of the present invention may beused to simultaneously deliver at least one active agent to a site.Agents such as antimicrobial agents, antifungal agents, antiviralagents, growth factors, angiogenic factors, anaesthetics,mucopolysaccharides and other proteins may be incorporated into thecompositions and devices for release into the environment. Especiallypreferred compositions and devices comprise a matrix that delivers bothoxygen and another active agent that has enhanced activity because ofthe presence of the oxygen. For example, certain therapeutic agents arerelatively inactive under reducing conditions but become significantlymore active when conditions become more oxygenated. Adjuvants and otheragents, such as those that boost the immune system, may also beincorporated into the devices of the present invention. A surprising andnovel aspect of embodiments having agents directly incorporated intomicro-cavities of the matrix is that the activities of the agents arenot altered by incorporation into the devices and that the agents areeffective upon their release.

In a further preferred embodiment, the devices of the present inventioncomprise a stranded configuration, wherein the strands extend from atleast one common region and the strands themselves comprise apolyacrylate matrix. In a preferred embodiment of the present invention,wound dressing devices of the present invention comprise novel strandedstructures made from a matrix suitable for application to broken skinand underlying tissues. The individual strands of the preferredembodiment may or may not have free floating ends, however, the uniquearrangement of the device allows it to maintain optimal oxygen tensionaround a wound site, absorb excess wound exudate, and simultaneouslyconform closely to the walls of the wound bed, in order to accelerateoverall wound healing. In addition to oxygen tension management,increased moisture absorption and the ability to deliver active agents,the individual strands of the devices may participate in mechanicaldebridement thereby accelerating the wound healing process.Additionally, preferred devices may be left in place for prolongedperiods between changes.

Accordingly, it is an object of the present invention to providecompositions and methods for the delivery of oxygen.

Another object of the present invention is to provide compositions,methods and devices for the treatment of compromised tissue.

A further object of the present invention is to provide compositions,methods and devices comprising materials that enable the management ofoxygen tension in a localized environment.

Still another object of the present invention is to provide devices thatdeliver oxygen to contacted tissues.

It is another object of the present invention to provide compositions,methods and devices that absorb excess moisture at a site.

Yet another object of the present invention is to provide compositions,methods and devices comprising incorporation of active agents.

It is another object of the present invention to provide compositions,methods and devices that promote autolytic debridement of compromisedtissues such as wounds.

A further object of the present invention is to provide compositions,methods and devices for external and internal compromised tissues.

Another object of the present invention is to prevent infection byproviding compositions, methods and devices that clean wound sites byremoving debris and contaminating material.

Still a further object of the present invention is to prevent infectionby providing compositions, methods and devices that provide oxygen toanerobic sites.

In yet another object of the present invention, compositions, methodsand devices are provided that deliver active agents, with or without thedelivery of oxygen, to compromised tissue sites, for the prevention ofinfection and to aid in healing.

Another object of the present invention is to provide compositions,methods and devices that deliver oxygen for the enhancement of theactivity of active or therapeutic agents.

Yet another object of the present invention is to provide compositions,methods and devices that deliver oxygen so that living organisms arekept alive.

Still a further object of the present invention is to providecompositions, methods and devices that deliver oxygen to tissues andorgans that are removed from their original source, such as tissues andorgans that are used for transplants.

A further object of the present invention is to provide compositions,methods and devices that deliver oxygen for packaging and shippingpurposes.

It is another object of the present invention to provide compositions,methods and devices that easily conform to the shape of a compromisedtissue site.

It is yet another object of the present invention to providecompositions and devices that are easily manufactured.

Still another object of the present invention is to providecompositions, methods and devices that may be easily removed fromcompromised tissues and replaced.

Yet another object of the present invention is to provide compositions,methods and devices that are compatible with injured tissue and do notinduce irritation or inflammation.

It is yet another object of the present invention to providecompositions, methods and devices that function to both absorb woundexudate and promote autolytic debridement.

Another object of the present invention is to provide compositions andmethods for making single unit construction devices having multiplestrands.

It is another object of the present invention to provide methods andcompositions for treating compromised tissues using devices thatfunction to both absorb moisture, deliver oxygen and deliver activeagents.

An object of the present invention to provide methods and compositionsfor treating wounds using wound dressing devices having active agentsincorporated therein.

Still another object of the present invention is to provide methods andcompositions for delivering active agents to wound sites and damagedtissue.

A further object of the present invention is to provide tissue contactmaterial that entraps gaseous oxygen or other gases to form a closedcell foam.

It is another object of the present invention to provide anoxygen-delivering tissue contact material that may be resorbed bytissues.

These and other objects, features and advantages of the presentinvention will become apparent after a review of the following detaileddescription of the disclosed embodiments and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph demonstrating the results of an experiment conductedto develop a method of determining total oxygen present in foamed oxygendressing. The graph shows that as a greater volume of distilled water isused for oxygen extraction, the calculated total oxygen concentrationreaches a plateau of approximately 6268.6 ppm.

FIG. 2 is a graph showing the rate of release of oxygen into varioussubstrates (water, saline and ABS) over time.

FIG. 3 is a graph showing the results of an experiment conducted inorder to determine whether an oxygenated matrix can donate biologicallyrelevant amounts of oxygen. In particular, the graph provides thesurvival time of goldfish in various sealed containers, with or withoutoxygen dressings.

FIG. 4 is a graph showing moisture uptake of different formulations ofoxygenated dressings.

DETAILED DESCRIPTION

The present invention comprises compositions, methods and devices forthe delivery of gases, preferably oxygen, or other active agents, to alocalized environment. Preferred embodiments of the present inventioncomprise devices comprising matrices that can deliver known amounts ofoxygen. The preferred embodiments are used in methods of treatment ofcompromised tissues and for methods of preserving life and maintainingthe state of extracted tissues or organs.

The present invention comprises compositions, methods and devices forthe treatment of compromised tissues. A preferred embodiment of thepresent invention comprises compositions and methods for treatingcompromised tissue comprising tissue contact materials that entrapoxygen within closed cell foam-like material capable of providing ormaintaining optimal oxygen tension at a compromised tissue site whileabsorbing excess fluid and optimizing the microenvironment to facilitatetissue repair and regeneration if needed. In addition, preferred devicesof the present invention have superior wound exudate/moisture absorptioncapabilities. In certain embodiments of the present invention, themethods, compositions and devices further comprise active agentsincorporated therein for release at the site. In a further preferredembodiment, the matrix composition comprises a polymer network with anon-gellable polysaccharide dispersed evenly throughout the network. Thematrices of this preferred embodiment provide a reliable and efficientmeans for maintaining oxygen tension, delivering active agents to thewound while at the same time providing a superior moisture regulationcapacity. In still another embodiment of the invention, the polymer is abioresorbable polymer suitable for topical and for implantationapplications.

The tissue contact material devices of the present invention are notrestricted by form or shape. The devices may be constructed in sheetstyle formats of various dimensions. Similarly, the materials can bemolded to conform to various shapes and contours as required by theintended use. Preferred embodiments of the present invention,particularly those used as wound dressing devices, may also take aparticular conformation. For example, a preferred embodiment of thepresent invention comprises a stranded configuration wherein theindividual strands extend from at least one common region and may havefree floating ends. This particular conformation is particularlysuitable for use in deeply cavitated wounds since the multiple matrixstrands enable the dressing to conform to individual and uniquely shapedwound areas. Furthermore, the devices accelerate wound healing bydisplacing and allowing for the removal of excess cellular exudate anddebris, thereby improving the rate of tissue repair and regeneration.

DEFINITIONS

The terms “a”, “an” and “the” as used herein are defined to mean one ormore and include the plural unless the context is inappropriate.

The term “compromised tissue” as used herein can be one or more tissuesand includes any organism, organ system, organ, tissue, cells orcellular components that is not in its normal metabolic state. Forexample, it means any tissue that has an abnormal blood supply, such asthat caused by ischemic conditions, hypoxic conditions, infarction,occlusions, blockages, or trauma. It also includes wounds and damage tostructural components.

The present invention is directed to compositions, methods and devicesfor the delivery of active agents, including gases. In particular,preferred embodiments are directed to delivery of oxygen to compromisedtissue. An example of preferred embodiments for treatment of compromisedtissues is the treatment of wounds. This example is for illustration,and should not be used in a limiting sense, and such preferredembodiments can be used for treatment of other types of compromisedtissue.

In addition to the management of excess moisture and infection around awound site, it is also important to maintain the appropriate oxygentension around the wound in order to facilitate effective healing.Several studies have shown that whereas oxygen tension in normal,uninjured tissue is approximately 80 to 100 mm Hg, the tension ininjured or damaged tissue is as low as 3 to 30 mm Hg. It has also beendemonstrated that levels of oxygen below 30 mm Hg are insufficient tosupport the process of wound repair. The novel methods and compositionsof the present invention provide unique tissue contact materials thatenable not only the absorption and management of wound exudate andmoisture, but importantly also enable the control of oxygen tensionaround a wound thereby facilitating efficient and superior tissue repairand regeneration. In alternative embodiments of the invention, the wounddressing device also comprises active therapeutic agents which arereleased and can be delivered in a controlled release manner. Therelease may be mobilized by a fluid phase that occurs as the matrixtakes up moisture from the environment or the contact substrate.

A preferred embodiment of the present invention comprises a suspensionof components for the formation of a polymer, such as acrylamide,together with various solvents such as lipids, water and alcohol. Moreparticularly, a preferred composition comprises a water suspensioncontaining acrylamide, bis acrylamide, glycerol, guar gum and isopropylalcohol. The suspension is mixed to completely hydrate the guar gum anddissolve the other ingredients. Subsequently, a solution such as TEMEDis sequentially added together with ammonium persulfate and sodiumcarbonate. The material is then mixed and poured into molds and allowedto gel. The gelled sheets are transferred into a drying oven fordehydration and are then rehydrated with a solution of hydrogenperoxide. After a ‘rest period’ of several hours, the foamed oxygencontaining material may then be cut to size and sterilized, for example,by electron beam irradiation.

A specifically preferred composition of the present invention is madeaccording to the following method. To 42.5 g H₂O add 2.47 g acrylamide,0.03 g his acrylamide, 2.5 g glycerol and 0.275 g guar gum suspended in0.275 g isopropyl alcohol. Mix the suspension for 3 hours to completelyhydrate the guar gum and dissolve the other ingredients. Sequentiallyadd to the mixture 0.026133 ml TEMED, 0.368 g ammonium persulfate and0.0888 g sodium carbonate. After 5 minutes of mixing the mixture ispoured into sheet molds and allowed to gel. The cued sheets are thentransferred into a drying oven at 45-50° C. to dehydrate below 10% w/wmoisture. The sheets are then rehydrated with a 10% solution of hydrogenperoxide at the ratio of 0.6 g sheet to 0.25 ml solution. The materialis allowed to stand for 12 hours. The foamed oxygen containing materialmay then be cut to size and sterilized by electron beam irradiation.

The chemical reaction between the hydrogen peroxide (second reactant)and the carbonate catalyst (reactant) causes the formation of water andgaseous oxygen which in turn causes the formation of closed cells orbubbles within the matrix. The cells contain an enriched concentrationof gaseous oxygen. The moisture in the walls of the matrix containdissolved oxygen.

As is known to those of skill in the art, the components listed above inthe preferred composition may be substituted by similar or equivalentmaterials. For example, the process may be carried out by substitutingthe carbonate reactant with other types of catalysts. Catalysts alsoinclude, but are not limited to, organic and inorganic chemicals such ascupric chloride, ferric chloride, manganese oxide, sodium iodide andtheir equivalents. Other catalysts, include, but are not limited toenzymes such as lactoperoxidase and catalase. Similarly, the secondreactant, hydrogen peroxide, may be substituted with other peroxides,including, but not limited to, ammonium peroxide and sodium peroxide.The present invention contemplates use of components that can generate agaseous element within the matrix and that are safe and effective foruse. For example, an acid catalyst can be incorporated in the matrixfollowed by perfusion of the matrix with a carbonate to generate carbondioxide gas within the matrix. Such materials are then used to buffersolutions or environments.

Further details concerning the methods and compositions of the presentinvention are found in the Examples below.

Active Agents

The active agents incorporated into the present invention are selectedon the basis of the use of the device. Active agents and their effectsare known by those skilled in the art and methods for including theseagents into the matrices of the present invention are taught herein. Thepresent invention contemplates the inclusion of one or more activeagents, depending on the intended use. The compositions and devices mayinclude one agent, such as oxygen, or may include multiple agents. Forexample, if the device is a matrix gel sheet placed in a tissue culturedish and is used to provide oxygen to the growing cells, the activeagents include oxygen and any other agents that aid the cells, such asantimicrobials to maintain sterility, or growth factors to aid in cellgrowth.

If the devices are used for topical treatments, such as treatments forcompromised tissues, the devices comprise active agents that aid intreatment of compromised tissues. For example, the devices are used forthe treatment of wounds, in skin healing or for cosmetic applications.The active agents aid and improve the wound healing process, and mayinclude gases, anti-microbial agents, including but not limited to,anti-fungal agents, anti-bacterial agents, anti-viral agents andanti-parasitic agents, mycoplasma treatments, growth factors, proteins,nucleic acids, angiogenic factors, anaesthetics, mucopolysaccharides,metals and other wound healing agents.

Active agents include, but are not limited to, gases, such as oxygen,nitrogen, carbon dioxide, and noble gases, pharmaceuticals,chemotherapeutic agents, herbicides, growth inhibitors, anti-fungalagents, anti-bacterial agents, anti-viral agents and anti-parasiticagents, mycoplasma treatments, growth factors, proteins, nucleic acids,angiogenic factors, anaesthetics, mucopolysaccharides, metals, woundhealing agents, growth promoters, indicators of change in theenvironment, enzymes, nutrients, vitamins, minerals, carbohydrates,fats, fatty acids, nucleosides, nucleotides, amino acids, sera,antibodies and fragments thereof, lectins, immune stimulants, immunesuppressors, coagulation factors, neurochemicals, cellular receptors,antigens, adjuvants, radioactive materials, and other agents that effectcells or cellular processes.

Examples of anti-microbial agents that can be used in the presentinvention include, but are not limited to, isoniazid, ethambutol,pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones,ofloxacin, sparfloxacin, rifampin, azithromycin, clarithromycin,dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline,ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine,sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone,paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet,penicillin, gentamicin, ganciclovir, iatroconazole, miconazole,Zn-pyrithione, and silver salts such as chloride, bromide, iodide andperiodate.

Growth factor agents that may be incorporated into compositions anddevices of the present invention include, but are not limited to, basicfibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF),nerve growth factor (NOF), epidermal growth factor (EGF), insulin-likegrowth factors 1 and 2, (IGF-1 and IGF-2), platelet derived growthfactor (PDGF), tumor angiogenesis factor (TAF), vascular endothelialgrowth factor (VEGF), corticotropin releasing factor (CRF), transforminggrowth factors α and β (TGF-α and TGF-β), interleukin-8 (IL-8);granulocyte-macrophage colony stimulating factor (GM-CSF); theinterleukins, and the interferons.

Other agents that may be incorporated into compositions and devices ofthe present invention are acid mucopolysaccharides including, but arenot limited to, heparin, heparin sulfate, heparinoids, dermatitinsulfate, pentosan polysulfate, chondroitin sulfate, hyaluronic acid,cellulose, agarose, chitin, dextran, carrageenan, linoleic acid, andallantoin.

Proteins that may be especially useful in the treatment of compromisedtissues, such as wounds, include, but are not limited to, collagen,cross-linked collagen, fibronectin, laminin, elastin, and cross-linkedelastin or combinations and fragments thereof. Adjuvants, orcompositions that boost an immune response, may also be used inconjunction with the wound dressing devices of the present invention.

Other wound healing agents that are contemplated in the presentinvention include, but are not limited to, metals. Metals such as zincand silver have long been known to provide excellent treatment forwounds. Delivery of such agents, by the methods and compositions of thepresent invention, provide a new dimension of care for wounds.

It is to be understood that in preferred embodiments of the presentinvention, the active agents are incorporated into compositions anddevices so that the agents are released into the environment. In topicaltreatments, the agents are then delivered via transdermal ortransmucosal pathways. The incorporated agents may be released over aperiod of time, and the rate of release can be controlled by the amountof cross-linking of the polymers of the matrices. In this way, thepresent invention retains its ability to affect the local environment,kill or inhibit microorganisms, boost the immune response, exert otheralterations of physiological function and provide active agents over anextended period of time.

In another embodiment of the present invention, active agents areincorporated directly into micro-cavities of the matrix of the wounddressing devices. The agents may be incorporated by absorption of agentsby the matrix, and preferably by incorporation during the polymerizationof the matrix. It is theorized that the release of the active agents maybe controlled via manipulation of concentration parameters, movement ofwater through the matrix and the degree of cross linking in the matrix.

Administering active agents for the treatment of compromised tissue byusing the compositions and methods of the present invention overcomesseveral of the problems of the prior art. First, the present inventionavoids the painful re-application of salves and ointments to compromisedtissues. The present invention also allows active agents to be delivereddirectly to the site to prevent the negative impact of system-widedelivery of the agents. In the case of deeply cavitated wounds, incontrast to the topical application of active agents, wound dressingcompositions and devices with active agents therein may be locateddirectly within the wound, providing a more effective delivery of theagents. Finally, in contrast to an injection of active agents, thepresent invention provides methods of administering active agentswherein the agents may be removed immediately from the compromisedtissue and the administration terminated.

Matrices

The present invention comprises a matrix material such as polyacrylamideand a non-gellable mucopolysaccharide, and most preferably, furthercomprises a catalyst (reactant) that generates a gas when reacted withanother component (second reactant), and further comprises one or moreactive agents incorporated therein. A unique feature of the matrices ofthe present invention is the formation of the foam or array of bubblesthat entrap the gas. The foam or bubbles are formed by the permeation ofthe second reactant added to the formed matrix that includes a reactant.When the two reactants interact, a reaction occurs that liberates gaswhich is entrapped within the matrix. For example, a matrix has acarbonate catalyst (a reactant) incorporated within it. The formedmatrix is then placed in the presence of the second reactant, hydrogenperoxide. A catalytic decomposition of hydrogen peroxide occursresulting in the liberation of oxygen gas which becomes entrapped asbubbles formed in situ. The hydrogen peroxide reactant is not part ofthe compounding of the matrix, but it is in the treatment after theformation of the matrix stock.

In preferred embodiments of the present invention, the matrix isflexible and elastic, and is a semi-solid scaffold that is permeable tosubstances such as aqueous fluids, inorganic salts, aqueous fluids anddissolved gaseous agents including oxygen. Though not wishing to bebound by any particular theory, it is thought that the substancespermeate the matrix through movement via intermolecular spaces among thecross-linked polymer.

Preferably, the matrix material is constructed from natural or syntheticpolymers. The matrix may also optionally include a non-gellablepolysaccharide. Natural polymers that may be used include, but are notlimited to collagen, gelatin, chondritin, calmodulin, cellulose, agar,agarose, animal hide, hyaluronic acid, dextran and alginate. Syntheticpolymers that may be used include, but are not limited to polylysine andother resorbable polymers, polyacrylamide, polymethacrylate,polyacrylate, polybuterate, polyurethane foam, polyether, silastic,silicone elastomer, rubber, nylon, vinyl or cross-linked dextran. Ifcross-linked dextran is used, it is preferred that the molecular weightof the dextran polymer is between 50,000 and 500,000. Additionally, thematrix material can be made from a combination of natural and syntheticpolymers, or mixtures of synthetic polymers or mixtures of naturalpolymers.

The most preferable non-gellable polysaccharide is a non-gellablegalactomannan macromolecule such a guar gum. A concentration range ofguar gum between approximately 0.005 to 53% w/w, preferably betweenapproximately 0.05 to 5% w/w, and most preferably between approximately0.25 to 1% w/w is generally sufficient. Other non-gellablepolysaccharides may include lucerne, fenugreek, honey locust bean gum,white clover bean gum and carob locust bean gum.

To decrease the permeability of the matrix, water loss control agentsmay be applied to the surface of the device. Application of water losscontrol agents is preferred since a decrease in the permeability of thedevice controls the loss of fluids. The preferred water loss controlagent is petrolatum, however, other water loss control agents such asglycolipids, ceramides, free fatty acids, cholesterol, triglycerides,sterylesters, cholesteryl sulfate, linoleic ethyl ester and silicone oilmay also be used. Additionally, the compositions and devices may have animpermeable sheet covering one or more surfaces to aid in control ofmoisture.

If desired, a plasticizer may also be added to the matrix material.Preferred plasticizers include glycerol and water, however, propyleneglycol and butanol may also be used. If glycerol is used, a range ofbetween approximately 0.25 to 25% w/w, preferably between 0.5 to 12%w/w, and most preferably between approximately 2.5 to 8% w/w isgenerally sufficient. The plasticizer may be added in the initialmixture of polymer and cross-linking agent.

If desired, a hydration control agent may be incorporated into thematrix. The preferred hydration control agent is an isopropyl alcohol,however, ethanol, glycerol, butanol, and propylene glycol may also beused. A range of isopropyl alcohol of between approximately 0.05 to 5%w/w, preferably between approximately 0.1 to 2.5% w/w and mostpreferably between approximately 0.25 to 1% w/w is generally sufficient.

The matrix of a preferred embodiment preferably comprises polymerizedchains of polyacrylamide, wherein the acrylamide monomers arecross-linked with a cross-linking agent, and a non-gellablepolysaccharide and an active agent or pharmaceutical may become directlyencapsulated into micro-cavities therein. A range of acrylamide betweenapproximately 0.5 to 50% w/w, preferably between approximately 1 to 25%w/w, and most preferably between approximately 2.5 to 10 w/w isgenerally sufficient.

The most preferable cross-linking agent is MN″-methylene-bisacrylamide,however other appropriate cross-linking agents such asbisacrylylycystamine and diallyltartar diamide may also be used. IfN,N′-methylene-bisacrylamide is used, a range of between approximately0.005 to 0.5% w/w, preferably between approximately 0.01 to 0.25% w/w,and most preferably between approximately 0.025 to 0.15% w/w isgenerally sufficient. Ammonium persulfate and TEMED may also be added tothe matrix. A range of ammonium persulfate between approximately 0.005%to 0.5% w/w, preferably between approximately 0.01 to 0.25% w/w, andmost preferably between approximately 0.025 to 0.1% w/w is generallysufficient. Additionally, a range of TEMED between approximately 0.001to 0.5% w/w, preferably between approximately 0.01 to 0.25% w/w, andmost preferably between approximately 0.025 to 0.15% w/w is generallysufficient.

A most preferred embodiment of the present invention comprises reactantsused to create the bubbles or foam that entrap gas. These reactants canbe catalysts that react with the second reactant to form the bubbles andentrap the gas. A most preferred reactant or catalyst is sodiumcarbonate. A range concentration of the reactant or catalyst is betweenapproximately 0.005% to 10.0% w/w, preferably between approximately 0.01to 5.0% w/w, and most preferably between approximately 0.1 to 5.0% w/wis generally sufficient. The most preferred concentration of sodiumcarbonate is approximately 1.0% w/w.

Incorporation of Active Agents

One embodiment of the matrices of the present invention can be found inU.S. Pat. No. 5,196,190 to Nangia et al., which is hereby incorporatedin its entirety. Nangia et al. teach a matrix composed of a natural orsynthetic polymer, a non-gellable polysaccharide, and a phospholipidbased drug delivery system. In particular, Nangia et al, teach a matrixcapable of drug delivery, wherein lipid vesicle liposomes containing adesired drug are incorporated into the matrix.

One problem with such a matrix, however, is the difficulty ofincorporating active agents into the liposomes because some agents maybe incompatible with liposome chemistry. Incorporation using liposomesis time consuming, expensive and sometimes unreliable because dispersionof the liposomes in the matrix is difficult to achieve and onceachieved, the liposomes may prematurely release costly agents due theliposomes' inherent instability. Another problem is that the prior artfails to teach a method of incorporating active agents into a devicewherein the release of the agent over time can be controlled through themanipulation of concentration parameters, movement of water through thematrix and the degree of cross linking in the matrix.

Preferred embodiments of the present invention however, address the needfor a less expensive, quicker, and more reliable method forincorporating a wider range of desired agents into wound dressingdevices. Preferred embodiments also provide a means to control therelease of the desired agents over time via manipulation ofconcentration parameters, movement of water through the matrix and thedegree of cross-linking in the matrix. In a preferred embodiment, thedesired agents may be directly incorporated into the matrix by addingthe agents into the initial formulation for the matrix prior tocross-linking. This method of incorporation is inexpensive, rapid andreliable, and most surprisingly, the incorporated agents are notaffected by the process of polymerization and retain their biologicalactivities. Additionally, active agents may be adsorbed or absorbed intoa preformed matrix. Some embodiments have the second reactant and theactive agent added to the preformed matrix, either simultaneously orsequentially, for perfusion within the matrix. The present inventionalso contemplates other methods of incorporation of active agents, suchenclosed within liposomes or other vesicles, other methods known tothose skilled in formulations for delivery of active agents.

Using preferred embodiments of the present invention, delivery of thedesired agents may be controlled by the use of movement of liquidthrough the matrix. Though not wishing to be bound by any theory, it istheorized that the liquid in a matrix of polymer and non-gellablepolysaccharide is either bound to the non-gellable polysaccharide or itis unbound in the polymer mass. Thus, it is theorized that the presentinvention uses the free liquid portion of the matrix as a generalsolvent and as a means to deliver desired agents. Soluble drugs areeasily dissolved in the free liquid portion, however slightly solubledrugs are ground to a fine powder and may require the use of a wettingagent such as glycerol or isopropyl alcohol or a surfactant such aspolysorbate, triton-X or sodium lauryl sulfate.

Once the desired active agent or agents are dispersed throughout thematrix, it is thought that a portion of the agent resides in thenon-gellable polysaccharide, while another portion of the agent isdissolved in the free liquid phase and moves freely through the matrix.The ability of the agent to move freely throughout the matrix in thefree liquid phase is useful in the agent delivery system of the presentinvention. Because the agent is dissolved in the free liquid phase, aconcentration gradient of the active agent is created between the matrixand the moisture of the environment. Therefore, when the matrix isplaced onto a moist surface, the soluble agent will move through thefree liquid phase toward the agent-free moisture, resulting in thedelivery of the agent. This movement of soluble agent further upsets theequilibrium between soluble and insoluble agents, and causes more agentto dissolve into the free liquid phase, thus causing more agent to bedelivered. Because preferred embodiments of the present inventionincorporate the desired agent directly into the matrix rather thanincorporating the drug into other delivery vehicles such as liposomes,the agent may be dissolved in the free liquid phase and reliablydelivered through the process described above. It is theorized thatgaseous agents, such as oxygen, are dissolved in the liquid of thematrix and are released from the matrix. Additionally, the gases may bereleased directly into the air of the environment, enriching theenvironment.

Delivery of the desired agents may also be controlled by the degree ofcross-linking in the matrix. As described above, the desired agents maybe added to the other components forming the matrix, prior to theaddition of the cross-linking agent. Subsequent addition of thecross-linking agent and concomitant polymerization results in both chainelongation of monomeric chemicals and cross-linking between chains ofmonomers. The combination of chains cross-linked together createsmicro-cavities wherein the desired agents are encapsulated. Bycontrolling the amount of cross-linking agent and the length of chainsof monomer, it is possible to regulate the size of the micro-cavities inthe polymer. Larger micro-cavities, produced by a lower degree ofcross-linking, allow for freer migration and quicker delivery of thedesired agent, whereas smaller micro-cavities increase the deliverytime. Although the liposome-based delivery system may also make use ofthe degree of cross-linking, the liposome itself acts as an additionalbarrier to delivery, making delivery less controlled and less reliablethan liposome-free delivery.

Stranded Structure

The compositions and devices of the present invention may take manyphysical forms, depending on uses of the compositions and devices. Apreferred shape is a gel sheet that can be cut or molded into any twodimensional shape. Other preferred embodiments are primarily constructedof thin strands of matrix suitable for placement into the wound bed orcavity. The preferred devices may be constructed from one or multiplestrands of matrix. When multiple strands are used in the construction,the strands are secured together by wrap, tie, glue, or alternatively bya continuous bridge of matrix between adjacent strands. Multiple strandsare secured together to minimize accidental loss during removal of thedressing from the wound bed. Typically, the strands of particular endsof the device may float free. The advantage of free floating strands isto enable the individual strands to access a maximum volume of the woundand thereby absorb the excess fluid, exudate and debris. The mechanicalaction of the free floating strands contributes to the trapping andremoval of cellular and wound debris. Concurrently the free floatingstrands also conform optimally with the contours of the wound surface tomaximize contact between the device and the wound bed. See U.S. Pat. No.5,928,174, herein incorporated by reference in its entirety.

The unique stranded embodiment is particularly desirable because itenables the device to maintain its integrity and also maximize thesurface area to volume ratio of its matrix. This is important since thematrix may be an absorbent material where a high surface area to volumeratio increases the rate of absorption, without increasing the overallabsorption capacity of the device.

In a preferred embodiment, the wound dressing is principally constructedof a “stranded” matrix, which allows for optimal contact between thestrands and the wound area. In addition, the stranded matrixconstruction maximizes the overall flexibility and pliability of thedressing. In embodiments of the device where multiple strands areemployed, the overall flexibility and conformational characteristics ofthe device are maintained by binding strands in only limited andrestricted areas. Minimal binding of the strands prevents the formationof rigid areas and allows for the effective and optimal utilization ofnumerous strands in a single device without adversely diminishingcontact with the surface of the wound bed.

Another advantage of the stranded matrix construction is the“semi-porous” quality of the wound dressing that allows for the removalof extraneous cellular matter resulting during the wound healingprocess. The air in the inter-strands area of the device serve as areservoir of space that may be displaced allowing for the removal ofexcess materials such as exudate fluid, debridement product and cellularexudate from the wound bed. As this region fills, the device may swellto provide “support” to the wound bed and surrounding tissues. A woundconstitutes damaged or “missing” tissue, and when tissue is missing, thesurrounding tissue may “collapse” or sag into the void. “Support” inthis context therefore, means the temporary filling of the void to holdthe surrounding tissue in place where it should reside.

Removal of debridement product and cellular exudate is furtherfacilitated by unbound, loose strands of the wound dressing devices.When placed upon a wound, the loose strands of the devices randomlyorient in the wound bed where the thin filamentous strands and freefloating ends contribute to mechanical debridement of necrotic slough.Since the strands are secured and bound in at least one region, amechanical union is formed, ensuring that all strands and necrotictissue accumulation in the inter-strand spaces are removed from thewound when the device is changed. By contributing to the removal ofextraneous wound products and cellular debris, the wound dressing devicepermits cleaning of the wound which in turn prevents and decreases thepossibility of infection and contamination.

A preferred stranded configuration of the present invention isparticularly desirable because the novel design provides a high surfacearea to volume ratio to maximize interchange between the matrix andwound moisture and wound debris. The multiple strands of the preferredconfiguration provide maximal inter-strand space to serve as a reservoirfor moisture, necrotic materials, or agents scheduled for delivery tothe wound bed. The superior moisture absorption and regulation capacityof the preferred embodiment equip the wound dressing devices for use onheavily to moderately draining wounds.

In one embodiment, the wound dressing device is constructed from amatrix composed of an absorbent synthetic polyacrylate material. Therate of absorption of polyacrylate is significantly increased by cuttingthe material into strands, which increases the surface area to volumeratio. This also provides a greater surface area for the release ofdissolved oxygen and other active agents from the device. Polyacrylatematerial is particularly suitable for the wound dressings of the presentinvention because it retains its integrity during interaction with woundexudate moisture, as well as with necrotic tissue and wound debris. Thewound dressing device of the present invention does not dissolve, gel orotherwise disintegrate during application to the wound. The preferredmatrix swells slightly during the absorption of moisture, causing thedevice to conform closely to the walls of the wound bed.

In a preferred embodiment, the polyacrylate matrix is cut intofree-floating strands bound together through a matrix-bridge in themid-region. This pattern of construction imparts a significantly highsurface area to volume ratio for rapid moisture movement within theabsorbent matrix.

Wound dressing devices of the present invention may be produced bycutting a desired design pattern from stock sheets of matrix material.For example, the material may be die-cut from stock sheets of anabsorbent polyacrylate wound dressing material. The stranded cut-out maythen be coated with an agent to prevent aggregation and tangling of thefree floating strands. Coating agents that may be used include, but arenot limited to, petrolatum, talcum, polyglycols, glycerol, propylene,glycol, vegetable oil, and animal oil. Following the steps of cuttingand coating, the material may be sterilized using sterilizationtechniques known in the art such as gamma radiation, steam and heatsterilization, electron beam or chemical sterilization (such as by useof ethylene oxide).

A preferred composition of the present invention is a matrix comprisinga polymer, a non-gellable polysaccharide, and one or more active agentsincorporated therein. A more preferred matrix comprises an acrylamidepolymer, guar gum, and one or more active agents incorporated therein. Amost preferred matrix comprises an acrylamide polymer, guar gum, and acatalyst that will support the decomposition of hydrogen peroxide tocause the formation of closed cells containing oxygen in the matrix. Inaddition the preferred embodiment may have one or more active agentsincorporated therein, and is formed into a stranded structure whereinthe strands are secured by at least one common region.

The wound dressing devices of the present invention may be used oninjured tissue and for bodily fluid drainages where control andmanagement of fluid and secretions is desired along with the delivery ofoxygen to the tissues. The term “bodily fluid,” as used herein,includes, but is not limited to, saliva, gingival secretions,cerebrospinal fluid, gastrointestinal fluid, mucous, urogenitalsecretions, synovial fluid, blood, serum, plasma, urine, cystic fluid,lymph fluid, ascites, pleural effusion, interstitial fluid,intracellular fluid, ocular fluids, seminal fluid, mammary secretions,vitreal fluid, and nasal secretions.

In particular, the wound dressing devices of the preferred embodimentsare especially applicable for usage on heavily exudating acute andchronic wounds for controlling accumulating exudate moisture, support ofthe wound bed and surrounding tissues and supplying oxygen. Importantly,the wound dressings are particularly effective for stimulating andsupporting autolytic debridement, inhibiting the growth of anaerobicbacteria and therefore accelerating the wound healing process.

In use, the wound dressing devices of the present invention are theprimary dressing placed in direct contact with the wound bed, or as nearas practical against the wound bed. The devices may serve as a packingmaterial and, if required, may be secured into position with anysuitable secondary wound dressing such as a wrap, tape, gauze, or pad.The dressings are temporary, however, and are not intended for permanentincorporation into the healed tissues. When necessary, the wounddressing devices are changed by first removing any over-dressingmaterial and then removing the device, whereby any accumulated necrotictissue and exudate is lifted away. The wound dressing devices of thepresent invention may be replaced by a fresh device or other suitablewound covering.

Additionally, wound dressing devices or contact tissue material devicesof the present invention may be made of resorbable materials, such aspolylysine or natural polymers. These devices may be left in place andare then resorbed by the body, instead of being removed. Such devicescan comprise active agents, such as gases or other agents such aspharmaceutical or anesthetic agents.

The devices may be placed in their entirety into a wound, placed incombination with additional bundles of the same design into the wound,or cut through the bridge between strands to reduce the size or numberof strands present in the wound.

The devices of the present invention may be cut, shaped and modified toaccommodate numerous uses and applications. For example, the devices maybe used as a gastric retrievable device, wherein a retrieval cord isattached to the device that is then swallowed. After absorption hastaken place, the devices may be retrieved and analyzed for content.

The devices may undergo a swelling action as they absorb exudatemoisture, however, they will not dissolve or disintegrate. The swellingaction displaces necrotic material from the wound surface and forces thematerial into the inter-strands regions of the device. The ladenmoisture content and the retention of moisture near the wound bed by theinvention contributes to stimulation of the autolytic debridementprocess whereby the body's own enzymes break-up necrotic tissue andcellular debris. Complete removal of the device occurs due to theconjoined nature of the device.

Other uses of the present invention include treatments for compromisedtissues. The compositions and devices of the present invention,comprising tissue contact material, may comprise a gas, such as oxygenin an oxygen delivery function tissue. Compositions and devices thatcomprise a gas delivery function, such as oxygen, and comprise otheractive agents are used to provide oxygen and other necessary agents,such as growth factors, nutrients or prevent infections or immunedestruction in the compromised tissues.

The present invention is used to deliver gases, preferably oxygen, toany desired environment. Such an environment may be a tissue culturevessel. For example, a sheet of the matrix of the present inventioncomprising oxygen can be added to the tissue culture vessel and thematrix will release oxygen, allowing for the growth of the tissueculture. Oxygen-delivery matrices can be used to deliver oxygen toaquatic organisms that are trapped within a closed environment. Additionof an oxygen-containing matrix provides a steady source of oxygen forthe organisms and prevents their death from suffocation. Additionally,oxygen-delivery matrices can be used to maintain oxygen levels intransplant organs or tissues and prevent their decay. For example, oncethe organ is removed, such as a kidney or heart donation, the organ iswrapped in a sheet of an oxygen-delivery matrix, placed in a coldenvironment and transported to the site where the transplant will occur.

The matrices of the present invention can deliver gases to organisms inneed of such gases. For example, hydroponic plants can be provided withcarbon dioxide or oxygen by the same or different matrices placed withinthe environment. Matrices can be placed in surrounding air or waterenvironments. Provision of gases using the matrices of the presentinvention has applications for use in outer space. Matrices can beplaced where delivery is desired and can be used for regular oremergency situations.

Oxygen-delivery matrices can be used to provide oxygen to anaerobicenvironments. In the presence of the matrix, anaerobic organisms will bekilled, providing treatments for infections due to anaerobic organisms.One use for an oxygen-delivery devices such as the present invention, isin the control and elimination of strict anaerobic bacteria. Anaerobicbacteria have low or no tolerance for elemental oxygen and rapidly dieif exposed to air or any other source of the gas. Pathogenic strains ofthese organisms tend to form localized anaerobic environments intissues. The insertion of the present invention into such environmentswould serve to oxygenate the surrounding areas and thereby cause thedeath of the pathogens. Therefore, such a device has utility in thetreatment of infectious gangrene.

Additionally, the oxygen supplied can be used to activate active agentsthat are not very active without oxygen and thus, these agents can beused in anaerobic environments. One or more matrices can be used toprovide both the oxygen and the agent activated by the oxygen to allowfor treatments of tissues that are not normally treated in this manner.One use for a tissue contact material for the delivery of oxygen tocompromised tissues is in adjunctive therapies that might be enhanced inactivity by an elevation of the local oxygen tension. As an example,certain therapeutic agents are relatively inactive under reducingconditions but become significantly more active when conditions becomemore oxygenated. The present invention therefore could be used todeliver a bolus of oxygen to the local environment such as the gut,vagina, or buccal cavity to enhance the activity of a therapeutic agent.

Other uses for provision of oxygen are contemplated by the presentinvention. Descriptions of uses provided herein are not to be limiting,but are illustrative of the many applications of the present invention.Other uses for the present invention include providing oxygen at adental site, or around a surgical site or an infarct site.Transportation of living organisms or biological specimens includes theneed to supply oxygen and the present invention is used in such amanner. For example, fish in an enclosed environment are maintained by amatrix of the present invention with oxygen incorporated therein. Othertransport needs, such as for transplant organs or for chemicals that canbe safely transported in the presence of an oxygen-rich environment, inthe presence of other gases that can be provided by the presence of amatrix, is contemplated by the present invention.

All patents and patent applications disclosed herein are herebyincorporated by reference in their entirety. All references listed orcited herein are incorporated by reference in their entirety. U.S. Pat.No. 5,928,174 issued on Jul. 27, 1999, along with U.S. patentapplication Ser. No. 09/191,223 filed on Nov. 13, 1998, and U.S.Provisional Patent Application Ser. No. 60/157,000 filed on Oct. 1, 1999are incorporated herein.

The foregoing description includes the best presently contemplated modeof carrying out the invention. This description is made for the purposeof illustrating the general principles of the inventions and should notbe taken in a limiting sense. This invention is further illustrated bythe following examples, which are not to be construed in any way asimposing limitations upon the scope thereof. On the contrary, it is tobe clearly understood that resort may be had to various otherembodiments, modifications, and equivalents thereof, which, afterreading the description herein, may suggest themselves to those skilledin the art without departing from the spirit of the present invention.

EXAMPLES Example 1 Preparation of Oxygen-Containing Closed Cell FoamDevice

The following experiment was conducted to make an oxygen containingclosed cell foam device out of polyacrylamide matrix. More specificallythe experiment involved use of hydrogen peroxide catalyzed by iodide inpolyacrylamide matrix to form oxygen foam.

ACRYDERM® matrix material is a unique matrix that is water absorbent,elastic, and oxygen permeable (see U.S. Pat. No. 5,928,174). In order toelevate oxygen levels in the matrix for use as an oxygen donator, sometreatment must be done post-polymerization, as oxygen quenches thepolymerization of polyacrylamide. As demonstrated below, this wasaccomplished by allowing hydrogen peroxide to be absorbed into thematrix, where it contacted a decomposition catalyst and formed oxygencavities.

Experimental Design:

1) A batch of ACRYDERM® matrix material was made incorporating 1% sodiumiodide pre-polymerization. To 42.5 g H₂O add 2.47 g acrylamide, 0.03 gbis acrylamide, 2.5 g glycerol and 0.275 g guar gum suspended in 0.275 gisopropyl alcohol. Mix the suspension for 3 hours to completely hydratethe guar gum and dissolve the other ingredients. Sequentially add to themixture 0.026133 ml TEMED, 0.368 g ammonium persulfate and sodium iodideto make 1% w/w. After 5 minutes of mixing the mixture is poured intosheet molds and allowed to gel. The gelled sheets are then transferredinto a drying oven at 45-50° C. to dehydrate to 10% to 20% of theoriginal weight. The sheets are then re-hydrated with a solution ofhydrogen peroxide, which causes the formation of the gas which istrapped in the matrix.2) After polymerization and drying of the matrix, an excess of 3%hydrogen peroxide was added to one piece (Matrix A), and a few drops ofhydrogen peroxide was added to another (Matrix B).3) Matrices were observed for foam formation.

Results

Hydrogen peroxide was quickly absorbed by the matrices and beganfoaming.

Matrix A: violent bubbling→large bubbles in matrix, white closed cellfoam formed as an end product

Matrix B: uniform small closed cells formed in the matrix.

Matrix B had better uniformity in bubble formation than Matrix A.However there was a NaI residue and yellow (yellow very slowly fades)coloration presumably due to the catalyst used.

Hydrogen peroxide was decomposed by iodide to water and oxygen, andiodine gas was released.

Conclusion

Bubbles, highly enriched for oxygen, can be formed in the elasticpolyacrylamide matrix by formulating the matrix with a hydrogen peroxidedecomposition catalyst and then allowing the polymerized matrix toabsorb hydrogen peroxide. The resulting reaction traps oxygen in thematrix. It is desired to have no residuals of this process left in thedevice, so an iodide to iodine gas decomposition is ideal due to theexodus of iodine gas from the device. Properties of the oxygenateddevice can be altered according the amount of peroxide applied.

Example 2 Comparison of Matrices

Formulated with Alternative Peroxide Catalysts

The following experiment was conducted to make closed cell foam devicesusing hydrogen peroxide and alternative catalysts to sodium iodide.

It has been demonstrated that a closed cell foam incorporating oxygenbubbles can be made using iodide as a hydrogen peroxide decompositioncatalyst. However, the catalytic reaction results in iodine gasformation, which does not dissipate quickly and leaves an odor. Also,residual sodium iodide in the device is not desired. Therefore, adecomposition catalyst that left either harmless residuals or noresiduals was desirable.

Experimental Design

1) 3 control ACRYDERM® matrices were used.2) Each was treated as follows: Soak 1 in a solution of a solution offerric sulfate to bring the final concentration to 2% Soak 1 in a sodiumcarbonate solution.3) Soak each matrix in excess 3% hydrogen peroxide.4) Observe matrices for foam formation, water solubility, moistureuptake, and volume increase.5) Test matrices 11 days later for residual hydrogen peroxide usingperoxidase assay.

Results

2% cupric chloride treatment→violent bubbling, destroyed matrix andmatrix became water soluble.2% ferric chloride treatment→bubbling, hard crusty dark brown, matrixbecame water soluble.Sodium carbonate→good, quick foam formation

-   -   X volume change=about 42 times larger than start size.    -   Moisture uptake=8.923 times original weight when placed        overnight in excess water.    -   Water solubility=not water soluble    -   Peroxide residue test=negative

Conclusion

If the decomposition of hydrogen peroxide was too strong, polyacrylamidewas degraded. This can be avoided by lowering the amount of hydrogenperoxide used or using an alternative decomposition catalyst, such assodium carbonate. Sodium carbonate as a catalyst formed a suitable foam,and decomposed into carbon dioxide gas, which is an acceptable residual.

Example 3 Rate of Release of Oxygen from Matrices into Water Substrate

The following experiment was conducted in order to test the rate ofrelease of oxygen from foamed devices into water using a membranedissolved oxygen electrode and meter.

As discussed above, topical application of oxygen to compromised tissuebenefits healing. Theoretically, oxygen in the foamed matrix dissolvesin the membrane moisture or exudate and enters the compromised tissue asdissolved oxygen. An in vitro simulation of this type of environment maybe manufactured using water sealed in a bottle to prevent the escape oringress of gases.

Experimental Design

The following steps were followed:1) Place 0.7 mL 10% hydrogen peroxide on 0.6 g of a previously madematrix that incorporates 1% sodium carbonate.2) 24 hrs later, place some of the foamed matrix in 110 mL distilledwater in a sealed glass bottle excluding any air bubbles.3) A dissolved oxygen probe was inserted in the bottle with a stir barand sealed excluding air.4) Under stirring, dissolved oxygen in ppm was recorded over time. Afterthe readings peak, open the lid on the bottle and monitor until oxygenlevels regain equilibrium.5) As a control, repeat the same procedure, using 1% sodium carbonatedevice non-foamed, or 350 μL 10% hydrogen peroxide solution in place ofthe foamed device.

Results

Oxygen Matrix min 24 hr 4 day 0 4 5 22 25 32 open open DO 8.4 9.5 1013.5 14 15+ 15+ equil

Hydrogen peroxide control min 0 20 40 60 175 DO 8.6 8.5 8.3 8.3 8.2

1% carbonate device control min 0 20 40 60 160 DO 8.6 8.5 8.3 8.3 8.2

Conclusion

Oxygen rapidly was transferred from the foamed oxygen device to thesubstrate. The controls demonstrated that residual catalyst or hydrogenperoxide was not responsible for this increase. The foamedoxygen-delivery matrix delivered oxygen to the local environment, andmaintained high oxygen levels in the substrate for at least a 24 hourperiod.

Example 4 Determination of Total Oxygen Content in Oxygen-DeliveryDevices

The following experiment was conducted in order to develop a method ofdetermining total oxygen present in the foamed oxygen devices.

In order to be an effective oxygen donator to tissue, the oxygen devicemust demonstrate that it can maintain release of oxygen over extendedtime periods. One indicator of the sustained, release potential of thedevice was a calculation of the overall amount of oxygen present in thedevice. The dissolved oxygen probe used for testing has a maximumdissolved oxygen reading of 15 ppm. Since the delivery of oxygen fromthe device had greatly exceeded this level in previous experiments, alarger quantity of substrate (distilled water) should be used todetermine total oxygen.

Experimental Design

The following steps were performed.1) Obtain 5 0.3 g pieces of oxygen-delivery matrix made previously byplacing 0.5 mL 10% hydrogen peroxide on 0.6 g pieces of 1% sodiumcarbonate ACRYDERM® matrix.2) Place each device in sealed glass containers of various sizes withdistilled water, excluding air bubbles (1200 mL, 635 mL, 120 mL, 60 mL).3) At t=24 hrs, record the dissolved oxygen in each bottle with themembrane electrode dissolved oxygen meter, under stirring.4) Calculate the total oxygen present in the device in ppm.

Results

mL DO ppm 1200 10.4 6268.6 635 11.8 5926.66 120 15.5 2600 60 18 1800 .344 44 theoretical maximum solubility of oxygen in water C 9 0

The results of this experiment are graphically provided in FIG. 1.

Conclusion

As the dissolved oxygen content approached 44 ppm (maximum solubility),the test chamber became more resistant to equilibration. As a greatervolume of distilled water was used for the oxygen extraction, thecalculated total oxygen concentration reached a plateau at levelsconsidered to be accurate. Therefore, total ppm oxygen in the device wasslightly greater than 6268.6 ppm for the formulation used.

Example 5 Oxygen Concentration Matrix

Accomplished by Varying Peroxide Concentrations

The following experiment was conducted in order to demonstrate thatoxygen devices may be made with different oxygen concentrations.

Varying the concentration of catalyst and hydrogen peroxide causesvariation in a range of physical characteristics. In order to optimizethe device's properties for use in different environments, it isadvantageous to be able to adjust the oxygen concentration of theoxygen-delivery device.

Experimental Design

The following steps were followed:1) Prepare 3 1% sodium carbonate ACRYDERM® matrix pieces.2) To a 0.6 g piece of each, add 0.5 mL 3% hydrogen peroxide, 10%hydrogen peroxide, or 30% hydrogen peroxide to make three foamedmatrices.3) 1 day after manufacture, place 0.28 g pieces of foamed matrix in asealed glass bottle with 600 mL distilled water, excluding air bubbles.4) Also add 3.75 cm×2 cm pieces of matrix to 250 mL distilled water.5) At t=24 hrs, take dissolved oxygen readings under stirring.

Results

Oxygen/g g mL 24 hr mg ppm ID device water ppm total total  3% .28 60010.7 1.02 3642 10% .28 600 13.4 2.64 9428 30% .28 600 16 4.2+ 15000+ c.28 600 9.0 0   0

Oxygen/cm² mL 24 hr mg ID area cm² water ppm total mg/cm²  3% 7.5 25011.3 .575 .076 10% 7.5 250 12.4 .85 .113 30% 7.5 250 13.1 1.025 .1366 cNA 250 9.0 0 0

Conclusion

By changing the concentration of hydrogen peroxide added to the device,a range of oxygen concentrations was achieved. A greater difference inconcentrations was seen in the per gram experiment, due to the fact thatan increase in oxygen is tied to an increase in volume of the device.However, on a per square area basis, a difference in oxygenconcentrations was also attained.

Example 6 Rate of Release of Oxygen into Various Substrates(ABS/Saline/Water)

The following experiment was conducted in order to measure the rate ofrelease of oxygen into various substrates.

Previous experiments demonstrated that oxygen is rapidly donated towater from the oxygen-delivery device. However, generally otherenvironment are more complex than distilled water, and are moredifficult to replicate in vitro. Two substrates tested were saline andmammalian blood serum.

Experimental Design

The following steps were followed:1) Obtain three foamed oxygen matrices made as follows: 0.5 mL 10%hydrogen peroxide on 0.6 g 1% sodium carbonate device. Area=6×3 cm.2) Prepare 3 250 mL glass bottles with distilled water, saline=0.85%NaCl, or adult bovine serum.3) Place 0.3 g oxygen device in bottle and monitor dissolved oxygen.Bottle sealed with probe and stir bar, no air bubbles.

Results

The results of this experiment are graphically provided in FIG. 2showing dissolved oxygen in ppm over time.

Conclusion

Although differences existed in the rate of release of oxygen intovarious substrates, the rate of donation into more complex media wasstill rapid. Equilibrium dissolved oxygen concentrations were lower inthe presence of salinity and other ions, explaining the lower initialdissolved oxygen levels and the slower rise in dissolved oxygen.

Example 7 Extending the Life of a Goldfish in a Sealed Container withOxyge-Delivery Device

The following experiment was conducted in order to determine whetheroxygenated matrix can donate biologically relevant amounts of oxygen.

Preliminary work has shown that closed cell foam formation resulted froma combination of hydrogen peroxide and a peroxide degradation catalyst.The closed cell foam should contain nearly pure oxygen gas. Experimentsusing an oxygen detecting probe strongly supported that conclusion.Further testing was necessary to confirm that the foamed matrix wascapable of donating biologically relevant oxygen. One approach was toshow that the matrix can sustain the life of a fish in water held, in asealed bottle.

Experimental Design

The following steps were followed:1) Place three weighed goldfish in 250 mL bottles distilled water.2) At t=0, place 1 g oxygen-delivery device in one bottle and seal allbottles excluding air bubbles.3) When one of the control goldfish dies (no oxygen-delivery matrix),open both control bottles, place 1 g oxygen device in the second controlgoldfish's bottle, (fish was dying), reseal with no bubble.4) Observe all goldfish for time of death and read dissolved oxygen.

Results

Place goldfish in water 8:30 am, Nov. 9, 1999. mL g ox death finalGold-fish water wt g device death hrs ppm 1 250 7.48 1 3:30 am 11-1019:00  2.5 2 250 6.75 0 3:05 pm 11-9 6:35 2.5 3 250 8.63 0 4:30 pm 11-98:00 2.5 Add 1 g oxygen device to #2 at 3:05 pm 11-9, dead 10:00 am11-10 → death hrs = 25:30

Results

The results of this experiment are graphically provided in FIG. 3showing survival time of goldfish in a sealed container, with or withoutoxygen device (1=7 hrs)

Conclusion

Dissolved oxygen delivered by the foamed oxygen matrix was sufficient tosustain the life of a goldfish for an extended period of time. Thegoldfish with oxygen-delivery matrix survived approximately 3.5 timeslonger than a goldfish with no oxygen device. This indicated that theoxygen-delivery matrix can donate oxygen to living tissue in therapeuticdoses over a desired time period.

Example 8 Moisture Uptake of Different Formulations of Oxygen-DeliveryDevice

The following experiment was conducted in order to determine moistureuptake properties of oxygen-delivery devices.

It has been shown that the foamed oxygen device can be manufactured tocontain varying levels of oxygen. A rise in oxygen concentrationcoincided with volume growth and a drop in density of the device. It wasdesired to determine that increased oxygen content does not affectmoisture uptake qualities in an adverse fashion.

Experimental Design

The following steps were followed:1) Prepare 3 1% sodium carbonate ACRYDERM® matrix material devices asdescribed in Example 1, except that instead of sodium iodide, 0.0888 gsodium carbonate is added, to make sodium carbonate at 1% w/w. Thepolymer mixture is allowed to gel, then dehydrated to approximately 20%of its original weight. The sample is then rehydrated with the hydrogenperoxide solution to allow formation of the oxygen gas and bubbles inthe matrix.2) To a 0.6 g piece of each, add 0.5 mL 3% hydrogen peroxide, 10%hydrogen peroxide, or 30% hydrogen peroxide to make three foameddevices.3) Record weight and area of oxygen devices.4) Immerse 3.6×4 cm samples of each device in 100 mL saline, incubate at35° C. for 30 min.5) Remove excess moisture by paper towel, weigh and record, returndevice to saline incubation.6) Repeat weighing procedure at 1.5, 2, 4, 6, 8, and 24 hrs.

Results

Moisture uptake over time in grams ID 0 hr .5 hr 1.5 hr 2 hr 4 hr 6 hr 8hr 24 hr  3% .5914 3.163 4.07 4.42 5.17 5.58 5.78 6.17 10% .2726 1.5721.94 2.06 2.27 2.37 2.44 2.50 30% .1294 .9076 1.00 1.03 1.09 1.16 1.171.24 Moisture uptake = final weight/start weight

Conclusion

Rate of moisture uptake and final moisture uptake per gram device wereequivalent for all oxygen formulations. Devices with higher oxygencontent weigh less per area, and so absorb fewer total grams water perarea.

Example 9 Stability of Oxygen Concentration in Oxygen-Delivery DeviceThrough E-Beam Irradiation

The following experiment was conducted in order to test the stability offoamed oxygen devices over time and through e-beam irradiation.

Medical devices must exhibit some level of sterility. A method ofsterilization ideal for polyacrylamide is electron beam irradiation.E-beam irradiation potentially could reduce substrates through electronbombardment, and products must be tested for resistance to possiblee-beam damage. In addition, the long term oxygen concentration stabilityof the oxygen-delivery device in packaging must be established. Foilpackaging was chosen due to its properties as an oxygen barrier.

Experimental Design

The following steps were followed:1) Prepare ten 10% foamed oxygen matrices (1% carbonate) as described inExample 8, but the hydrogen peroxide concentration is a 10% solutionrather than the typical 3% solution.2) Package in foil. 11-17-99.3) Send five to e-beam 11-24-99.4) Place 0.3 g of e-beamed and control oxygen devices in 600 mLdistilled water each in sealed glass bottles, excluding air bubble.11-29-995) At t=24 hrs, read dissolved oxygen.

Results

Sterilization lot-4-993043 25-33.1 kGy dose PO#624

11-29 E-beam→11.5 ppm

11-29 control oxygen→11.5 ppm11-29 control ACRYDERM® matrix material→9.0 ppm

Conclusion

E-beam irradiation had no discernable effect on the condition or oxygenconcentration of the foamed oxygen-delivery devices. Moreover, devicespackaged in foil showed no significant loss of oxygen over a 12 day timeperiod.

Example 10 New Formulations of Oxygen-Delivery Devices

The following experiment was conducted in order to determine alternativeoxygen-delivery device formulations to improve general characteristics.

In order to improve several characteristics of the original foamedoxygen matrix, such as flexibility, stability, moisture uptake, orelasticity, certain variables were manipulated. These included catalystvariations and changes in the concentration of key components. A widerange of devices may be manufactured in this manner.

Experimental Design

The following steps were followed:1) Prepare 8 ACRYDERM® matrix material devices, containing:

A. 1% sodium carbonate, undried gel

B. 0.5% sodium carbonate, 0.5% sodium bicarbonate

C. 1% sodium carbonate, 40% less glycerol than the standard Acrydermmatrix

D. 1% sodium carbonate, 30% less glycerol

E. 1% sodium carbonate, 50% less glycerol, 50% less guar gum

F. 1% sodium carbonate, no guar gum

G. 1% sodium carbonate, 25% more guar gum

H. 1% sodium carbonate, 0.01% sodium iodide.

The standard matrix composition is described in Example 1 and thecarbonate amounts are given in Example 8. Changes described herein arechanges from the standard matrix composition.2) Add 025 mL of 20% hydrogen peroxide to 0.6 g each matrix3) Matrices were observed for foam formation.

Results

ID Results A. very big bubbles, less flexible B. normal C. slightly toostiff, not flexible D. slightly stiff, good E. stiff, but still good,more clear F. more flexible, clear, big bubbles G. non uniform bubbles,lots of smaller bubbles H. Very quick foam formation, non uniformbubbles

Conclusion

Changing key components of the ACRYDERM® matrix material batch resultedin different final oxygen levels. Some components, such as guar gum, maynot be a necessary component. In fact, a good oxygen-delivery matrix maycomprise a flexible, solvent-absorbent polymer, peroxide, and adecomposition catalyst.

Example 11 Oxygen Entrapment in Non-Polyacrylate Substrates

Polyacrylate is a non-resorbable substrate which limits its use totopical or non-implantable applications wherein the matrix can beremoved. Numerous other polymerized materials may form closed cell foamsto encase oxygen gas but have the added advantage of beingbiodegradable, i.e., resorbable. The purpose of this experiment was showthe feasibility of entrapment of oxygen gas into other substrates.

Experimental Design:

Gelatin, agar and agarose granuals were dissolved in concentrationsranging from 1 to 5% w/w in water by heating. Various samples of thesolutions then received sodium carbonate along with guar gum andglycerol before being poured into molds to gel as sheets. After the gelshad set they were dehydrated and then re-hydrated with a hydrogenperoxide solution.

Results

All of the samples formed closed cell foam like materials as long as thecatalyst was present in the polymer. The results are summarized in thetable.

Polymer [Guar Substrate Concentration Gum] [Glycerol] Properties Gelatin3% Yes Yes Pliable closed cell foam Gelatin 3% No Yes Pliable closedcell foam Gelatin 3% Yes No Brittle closed cell foam Gelatin 1% Yes YesVery fragile closed cell foam Agar 5% Yes Yes Pliable closed cell foamAgar 5% No Yes Pliable closed cell foam Agar 5% Yes No Brittle closedcell foam Agar 1% Yes Yes Very fragile closed cell foam Agarose 5% YesYes Pliable closed cell foam

Conclusion

These experiments showed that a catalyst was incorporated into abiodebradeable matrix to support the degradation of hydrogen peroxideand that polymers other than polyacrylamide polymers could be used. Insuch a construct, the addition of hydrogen peroxide to the polymerizedmaterials caused the formation of oxygen gas which became entrappedwithin the polymer scaffold to form a closed cell foam.

It should be understood that the foregoing relates only to preferredembodiments of the present invention and that numerous modifications oralterations may be made therein without departing from the spirit andthe scope of the invention as set forth in the appended claims.

1-20. (canceled)
 21. An oxygen-delivery wound treatment device, thedevice comprising: a) a formed biocompatible matrix comprising: apolymer, wherein the polymer comprises polyacrylamide, gelatin, agar,agarose, or a combination thereof; and a catalyst, wherein the matrixincludes closed cells and walls; b) gaseous oxygen, wherein the gaseousoxygen is contained in the closed cells; and c) dissolved oxygen,wherein the dissolved oxygen is present in moisture in the walls,wherein the gaseous oxygen and the dissolved oxygen are produced when aperoxide is reacted with the catalyst.
 22. The device of claim 21,wherein the catalyst is present in the matrix in an amount ranging fromabout 0.005 wt. % to about 10 wt. % based on the total weight of thematrix.
 23. The device of claim 21, wherein the catalyst comprisessodium carbonate, cupric chloride, ferric chloride, manganese oxide,sodium iodide, lactoperoxidase, or a combination thereof.
 24. The deviceof claim 21, wherein the peroxide comprises hydrogen peroxide, ammoniumperoxide, sodium peroxide, or a combination thereof.
 25. The device ofclaim 21, further comprising at least one active agent.
 26. The deviceof claim 21, wherein the matrix comprises a stranded configuration. 27.The device of claim 21, further comprising a water loss control agent,wherein the water loss control agent comprises petrolatum, glycolipids,ceramides, free fatty acids, cholesterol, triglycerides, sterylesters,cholesteryl sulfate, linoleic ethyl ester, silicone oil, or acombination thereof.
 28. The device of claim 21, further comprising aplasticizer, wherein the plasticizer comprises glycerol, water,propylene glycol, butanol, or a combination thereof.
 29. The device ofclaim 21, further comprising a hydration control agent, wherein thehydration control agent comprises isopropyl alcohol, ethanol, glycerol,butanol, propylene glycol, or a combination thereof.
 30. The device ofclaim 21, further comprising a non-gellable polysaccharide.
 31. Thedevice of claim 30, wherein the non-gellable polysaccharide comprisesguar gum.
 32. The device of claim 21, wherein the polymer comprisespolyacrylamide.
 33. The device of claim 32, wherein the polyacrylamideis cross-linked.
 34. The device of claim 21, wherein the devicecomprises residual peroxide.
 35. The device of claim 21, wherein thedevice comprises residual catalyst.
 36. The device of claim 21, whereinthe oxygen-delivery wound treatment device maintains delivery of oxygenfor at least 24 hours
 37. An oxygen-delivery wound treatment device, thedevice comprising: a) a formed biocompatible matrix comprising: apolymer, wherein the polymer comprises polyacrylamide, gelatin, agar,agarose, or a combination thereof; and a catalyst, wherein the matrixincludes closed cells and walls; b) gaseous oxygen, wherein the gaseousoxygen is contained in the closed cells; and c) dissolved oxygen,wherein the dissolved oxygen is present in moisture in the walls,wherein the gaseous oxygen and the dissolved oxygen are produced when aperoxide is reacted with the catalyst, wherein the oxygen-delivery woundtreatment device maintains delivery of oxygen for at least 24 hours. 38.The device of claim 37, wherein the catalyst is present in the matrix inan amount ranging from about 0.005 wt. % to about 10 wt. % based on thetotal weight of the matrix.
 39. The device of claim 37, wherein thecatalyst comprises sodium carbonate, cupric chloride, ferric chloride,manganese oxide, sodium iodide, lactoperoxidase, or a combinationthereof.
 40. The device of claim 37, wherein the peroxide compriseshydrogen peroxide, ammonium peroxide, sodium peroxide, or a combinationthereof.
 41. The device of claim 21, wherein the catalyst is inorganic.42. The device of claim 37, wherein the catalyst is inorganic.